4-Methyl-2-oxo-cyclopentaneacetic acid prostaglandin intermediates

ABSTRACT

New optically active intermediates and processes for producing optically active prostaglandins which are useful for various therapeutic purposes such as antisecretory agents, cardiovascular agents, antiulcerogenic agents and as agents for inducing labor or terminating pregnancy in pregnant females.

This is a division of application Ser. No. 279,492 filed July 1, 1981,now U.S. Pat. No. 4,390,718.

BACKGROUND OF THE INVENTION

Prostaglandins are well known therapeutic agents which have been used ascardiovscular agents, as agents to induce labor or terminate pregnancyin pregnant females, as antisecretory agents for preventing hyperacidityand as anti-ulcerogenic agents.

Prostaglandins having known therapeutic uses have been disclosed in U.S.Pat. No. 4,052,446, Holland et al., said prostaglandins having thefollowing general formula: ##STR1## wherein R is hydrogen or loweralkyl, R₁ is lower alkyl, hydrogen, carboxy, lower alkoxy or carbonyl,R₂ is hydrogen or lower alkyl; R₃ is hydrogen, lower alkyl or fluoro.

Processes for the preparation and the administration of therapeuticallyeffective prostaglandins are disclosed in the above cited U.S. patent aswell as in U.S. Pat. Nos. 4,190,587 and 4,154,963.

SUMMARY OF THE INVENTION

New optically active intermediates and processes thereto are providedfor use in synthesizing2-alpha-carboxymethyl-3-beta-nitromethyl-4-alpha-methylcyclopentan-1-one of formula ##STR2## which is a known intermediate fortherapeutically active prostaglandins of the formula: ##STR3## wherein Ris hydrogen or lower alkyl, R₂ is hydrogen or lower alkyl and R₃ ishydrogen, lower alkyl or fluoro;

In accordance with this invention the compound of formula VIII, a knownintermediate of prostaglandins of formula IX, is produced via thereaction of 3-methylcyclopentenone and a glyoxylate compound of formula:##STR4## wherein R is as above.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to new optically active intermediates andto new processes for producing said intermediates from3-methylcyclopentenone and a compound of formula II.

The term "lower alkyl" includes both straight chain and branched chainalkyl groups having from 1 to 7 carbon atoms such as methyl, ethyl,propyl, butyl, n-butyl, etc. The preferred alkyl groups are methyl,ethyl and n-butyl.

The following reaction scheme presents the process and intermediates inthe present invention. In the scheme the reaction processes aredesignated as steps 1-6, while the formulas representing the startingmaterials, intermediates and end products are designated by Romannumerals I-VIII, and R is as defined earlier. All the compounds havingan asymmetric carbon atom can be produced by the reaction processes ofthis scheme as racemic mixtures. It is preferred that these racemicmixtures be resolved in order to obtain optically active compounds, thepreferred compounds of the present invention. These racemic mixtures maybe resolved at the various steps in the process of this invention bymethods well known in the art for resolving an acid or ester, providing,thereby, the optically pure enantiomers. If desired the acid of formulaVIII, for example, may be resolved in accordance with the proceduredisclosed in U.S. Pat. No. 4,154,963. ##STR5##

In accordance with the above reaction scheme, the process of the presentinvention provides the compound of formula VIII from the compounds offormulas I and II.

The starting materials for step 1 of the reaction scheme are3-methylcyclopentenone (formula I) and a glyoxylate compound of formulaII or a compound capable of liberating a glyoxylate compound of formulaII. These starting materials react by an aldol condensation to form thecompound of formula III. Any conventional compound liberating glyoxylatecan be utilized as a starting material in this process. The preferredglyoxylates are methylglyoxylate, ethylglyoxylate and n-butylglyoxylateor a compound liberating glyoxylate, such as polymers of theaforementioned glyoxylates. The ratio of these starting materials in thereaction mixture is not critical. It is preferred, however, that theglyoxylate be stoichiometrically in slight excess of the3-methylcyclopentenone.

In the most preferred embodiment of this invention,3-methylcylopentenone is reacted in step 1 with ethyl-glyoxylate in asolvent containing a suitable catalyst. Any conventional inert organicsolvent may be used. Among these solvents are toluene, tetrahydrofuran(THF), dimethylformamide (DMF), dimethylsulfoxide (DMSO),dimethoxyethane, (DME), etc. The preferred solvent is toluene. Theamount of solvent used is not critical and can be any amount customarilyrecognized in the art for carrying out such a reaction. It is preferredthat the solvent, such as toluene, be in an amount sufficient todissolve all the reacting components of step 1.

A suitable catalyst may be any organic heterocyclic amine base such asmorpholine, piperidine, pyrrolidine, pyridine or proline, with thepreferred catalysis being morpholine. Low concentrations of catalyst arepreferred such as in the range of from about 0.001% to about 10% byweight of the 3-methylcyclopentenone in the reaction mixture, with thepreferred concentration being 0.05% to 5% by weight, especiallypreferred is 3%.

Temperature and pressure are not critical for the reaction of step 1 butit is preferably carried out under an inert gas at atmospheric pressureand temperatures of about 20° C. to reflux. It is most preferred thatstep 1 be carried out at the boiling point (reflux) of the reactionmixture, to provide during the reaction a monomeric glyoxylate from anypolymeric form of the glyoxylate being used, resulting thereby in highyields of product. The inert gas used in carrying out this reaction andall subsequent reactions as indicated by the above scheme can be anyconventional inert gas such as nitrogen or argon. The product producedin step 1 is the compound of formula III.

The condensation product, the compound of formula III, as well as theother compounds indicated in the process, may be isolated, if desired,by conventional methods well-known in the art such as distillation andchromatographic methods such as column, paper, high pressure liquidchromatography or gel filtration and the like.

Step 2 can be carried out using the isolation compound of formula III orpreferably using the final reaction residue mixture of step 1 afterconventional evaporation. In step 2 the double bond in the ring of theproduct of formula III is hydrogenated by any method of hydrogenatingdouble bonds, such as by utilizing an hydrogenating catalyst such aspalladium on charcoal in the reaction mixture carrying out thisreaction.

In step 3 the compound of formula IV is dehydrated by a suitabledehydrating agent to give the compound of formula V. The dehydrationprocess as well as the dehydrating agent may be any which are well knownin the art. For example dehydration may be accomplished in aconventional manner by adding a solution of p-toluenesulfonic acidmonohydrate in toluene or P₂ O₅ -alumina (neutral) in toluene. Otherdehydrating agents known in the art may be conventionally used, such asFeCl₃, FeCl₃ -silica gel, BF₃, Et₂ O, MgO, MgO-molecular sieves, P₂O₅,P₂ O₅ -silica gel, anhydrous P₂ O₅ --Al₂ O₃, Na₂ CO₃, Ac₂ O--HOAc,Al₂ O₃,CH₃ SO₂ CL-pyridine, NaOAc, CH₃ SO₂ Cl--Et₃ N and perchloricacid. Any of the conditions conventionally used with these dehydratingagents can be used in carrying out this reaction.

In step 4 the compound of formula V is isomerized to provide thecompound of formula V. The reaction of step 4 may be carried out byisomerizing in an inert organic solvent the compound of formula V usinga transition metal or salt or oxide thereof as a catalyst. It ispreferred that the reaction be carried out at elevated temperatures,especially at the boiling point of the solvent. In carrying out thisreaction any lower alkanol may be used as the solvent. Among thepreferred lower alkanols are included both straight and branched chainlower alkanols having from 1 to 7 carbon atoms, such as methyl alcohol,ethyl alcohol, butyl alcohol, propyl alcohol, etc. Ethanol is especiallypreferred.

This isomerization of the double bond in the compound of formula V togive the compound of formula VI may also be effected by replacing thetransition metal or salt or oxide thereof with an inorganic or organicbase as catalyst. For example the isomerization may be effected usingpyridine as a catalystic solvent or using an alkylamine such as adimethylaminopyridine and a solvent such as toluene or hexane ascatalysts. For such a reaction the preferred temperature is from 50° C.to 130° C.

Any transition metal in pure form or salts thereof in hydrated ordehydrated form may be used in step 4 as catalysts, such as RhCl₃.3H₂ O,PdCl₂, Rh,Pd, PdCl₂ (C₆ H₅ CN)₂, Rh on graphite, ZnO, etc. The preferredcatalyst is RhCl₃.3H₂ O. It is preferred that the catalyst be from about5% to about 20% by weight of the solvent. It was surprisingly found thatthe use of a catalyst lowered the production of unwanted isomers and theamount of reaction time. By this procedure the compound of formula VIwas obtained in the absence of other significant isomers when theconcentration of catalyst was 5% or more by weight of the solvent. Usingless catalyst required prolonged reaction times (3-4 days) and producedcompound of formula VI as a mixture with other related isomers.

The compound of formula VII can be obtained in step 5 by treating thecompound of formula VI with nitromethane in the presence of a base. Forcarrying out the reaction of step 5 any conventional base may be used.The preferred bases are the lower alkoxides, particularly the alkalimetal lower alkoxides, and the amines, particularly tertiary andquaternary amines, and pyridine. An especially preferred base isbenzyltrimethylammonium hydroxide. In carrying out the reaction of step5, temperature and pressure are not critical but the reaction ispreferably carried out in an inert atmosphere such as under nitrogen andat elevated temperatures, especially preferred is 65°-70° C.

The compound of formula VIII,2-alpha-carboxymethyl-3-beta-nitromethyl-4-alpha-methylcyclopentan-1-one, is a known compound, disclosed for instance in U.S.Pat. No. 4,154,963 and may be obtained in step 6 by a hydrolysis ofcompound of formula VII. Step 5 may continue to step 6 using theisolated compound of formula VII or preferably using the final reactionresidue mixture of step 5 after conventional evaporation. In carryingout the hydrolysis of the compound of formula VII any conventionalmethod of hydrolysis may be used. Hydrolysis is preferably carried outusing a dilute aqueous mineral acid such as sulfuric acid or in a diluteaqueous alkali such as sodium hydroxide. Hydrolysis in dilute sodiumhydroxide is most preferred. The temperature and pressure of thehydrolysis is not critical but preferrably the reaction is carried outat atmospheric pressure under nitrogen at slightly elevated temperatureof about 40° C. The compound of formula VIII may then be obtained byconventional extraction and filtration methods.

The racemic products and intermediates of this invention can be resolvedinto their optically active components by a number of methods ofresolution well know in the art. The compounds which are acids may betreated with an optically avtive base in a conventional manner toproduce diasteroisomeric salts which can be separated bycrystallization.

The present invention is further exemplified by the following examples.

EXAMPLE 1

Step 1 using Ethyl Glyoxylate (also known as oxoacetic acid ethylester):

A 2-L, round bottomed flask equipped with a mechanical stirrer andnitrogen inlet tube was charged with 48 g (0.5 M) of freshly distilled3-methyl-2-cyclopenten-1-one (bp 73°-74° C./16 mm Hg), 66.4 g (0.65 M)of freshly distilled ethyl glyoxylate (bp 126°-130°/760 mm Hg), 1.31 g(0.015 M) of morpholine, and 650 ml of toluene. The resulting reactionmixture was boiled under reflux for 21 hours and cooled to roomtemperature and thereafter evaporated to provide a crude material. Thiscrude material was used directly in the hydrogenation process of Example3. The crude material contains the productalpha-hydroxy-(4-methyl-2-oxo-3-cyclopenten-1-yl-acetic acid ethyl esterwhich may be obtained by distillation of the crude material to give theproduct as a viscous oil, bp 150° C./10 mm Hg.

EXAMPLE 2

Step 1 using n-Butyl Glyoxylate:

Into a 3-L, 3-necked, round-bottomed flask equipped with a mechanicalstirrer, condenser, and a nitrogen inlet tube were added 96.1 g (1.0 M)of freshly distilled 3-methyl-2-cyclopenten-1-one, 169.0 g (1.3 M) offreshly distilled n-butyl glyoxylate, 1.3 L of toluene and 2.61 g (0.03M) of morpholine. The resulting reaction mixture was heated at refluxfor 24 hours and then evaporated in vacuo to give as product 263.0 g ofcrude racemic alpha-hydroxy-4-methyl-3-oxo-3-cyclopentene-1-acetic acidbutyl ester as a viscous, light brown oil, bp 130° /0.05 mm, for use inExample 4.

EXAMPLE 3

Step 2, Hydrogenation process (Ethyl Ester):

99.1 g of crude alpha-hydroxy-(4-methyl-2-oxo-3-cyclopenten-1-yl)-aceticacid ethyl ester (as prepared in Example 1) in 882 ml of toluene washydrogenated over 9.91 g of 10% by weight of palladium and 90% by weightof charcoal at room temperature and 25-50 psi. After hydrogen uptake hadceased, the catalyst and solvent were removed by filtration andevaporation to give 101 g of a viscous, amber-colored oil. This oil isdistilled to provide the productalpha-hydroxy-4-methyl-2-oxo-cyclopentane acetic acid ethyl ester, bp96°-111°/0.05 mmHg, for use in Example 5.

EXAMPLE 4

Step 2 Hydrogenation Process (Butyl Ester):

226 g of alpha-hydroxy-4-methyl-3-oxo-3-cyclopentene-1-acetic acid butylester (as prepared in Example 2) in 2 L of toluene (as solvent) washydrogenated over 22.6 g by weight of palladium and 90% by weight ofcharcoal (as catalyst) at room temperature and 25-50 psi. The catalystand solvent were removed by filtration and evaporation to provide 251 gof a reddish brown, viscous oil which was distilled to provide racemicalpha-hydroxy-4-methyl-2-oxo-cyclopentene acetic acid butyl ester, bp110°-117° C./0.05 mmHa for use in Example 6.

EXAMPLE 5

Step 3. Dehydration (Ethyl Ester):

A 2-L, 3-necked, round-bottomed flask equipped with a mechanicalstirrer, thermometer, a Dean-Stark trap and condenser was charged with62.9 g (0.314 M) of (alpha-hydroxy-4-methyl-2-oxo-cyclopentane aceticacid ethyl ester (as prepared in Example 3) in 940 ml. of toluene and3.0 g (0.015 M) of p-toluenesulfonic acid monohydrate. The resultingreaction mixture was stirred under nitrogen at 80° for 2 hours and thenat 85° for a further 2 hours with azeotropic removal of water. Themixture was cooled to room temperature, washed successively with 250 mlof brine, 250 ml of water, dried (MgSO₄), and evaporated to give 62.0 gof a dark reddish-brown oil which was distilled to provide a product asa pale homogeneous yellow oil, bp 68°-88° C./0.05 mm Hg, identified as4-methyl-2-oxo-cyclopentylidene acetic acid ethyl ester which was usedin Example 7.

EXAMPLE 6

Step 3 Dehydration (n-Butyl Ester):

Into a 5-L, 3-necked, round-bottomed flask equipped with a condenser,thermometer and nitrogen inlet were added 154.8 g (0.68 M)alpha-hydroxy-4-methyl-3-oxo-cyclopentene acetic acid butyl ester (asprepared by Example 4), 2.3 L of toluene, and 12.9 g (0.068 M) ofp-toluenesulfonic acid monohydrate. The resulting reaction mixture wasstirred at 75°-78° C. for 61/2 hours under nitrogen. When the reactionwas complete, the mixture was cooled to 15° C., poured into a separatoryfunnel, washed with three 1-L portions of a total of 3 L of water, dried(MgSO₄) and evaporated to give 153 g of the homogeneous4-methyl-3-oxo-cyclopentylidene acetic acid butyl ester bp 82°-84°C./0.05 mm Hg, as a red oil for use in Example 8.

EXAMPLE 7

Step 4, Isomerization (Ethyl Ester):

A 1-L, 3-necked, round-bottomed flask equipped with a mechanicalstirrer, condenser, and a nitrogen inlet tube was charged with 40.1 g of4-methyl-2-oxo-cyclopentylidene acetic acid ethyl ester (as prepared byExample 5), 500 ml of 90% aqueous ethanol and 2.0 g of rhodium chloridetrihydrate. The resulting reaction mixture (under N₂) was boiled underreflux for 14 hours, and then evaporated in vacuo. To the residue wasadded 200 ml of saturated brine; the mixture was then stirred for 15minutes and extracted with three 200-mL portions, a total of 600 ml ofdiethyl ether. The extract was dried (MgSO₄), filtered, and the filtratewas slurried with 100 g of Grade I alumina. The alumina was filtered andwashed with 400 ml of ether. The filtrate and washing were evaporated togive 31 g (77%) of product, 3-methyl-5-oxo-1-cyclopentene-1-acetic acidethyl ester, as a colorless oil, bp 90°/0.05 mmHg, which is relativelyunstable and should be refrigerated under N₂ for storage. This productwas used in Example 10.

EXAMPLE 8

Step 4 Isomerization (n-Butyl Ester):

A 3-L, round-bottomed flask equipped with a mechanical stirrer,condenser, and a nitrogen inlet tube was charged with 103.8 g (0.495 M)of 4-methyl-2-oxo-cyclopentylidene acetic acid butyl ester (as preparedby Example 6), 1.25 L of 90% aq. ethanol, and 5.19 g of rhodium chloridetrihydrate. The stirred mixture, under nitrogen, was heated at refluxfor 24 h, cooled to 40° C., and evaporated in vacuo to give a viscous,red oil. This was diluted with 1.0 L of 20% brine and extracted with3×600 ml of toluene. The combined extracts were dried with MgSO₄,concentrated to about 500 ml, and slurried with 200 g of neutral alumina(Grade I). The alumina was removed by filtration and washed three timeswith 250 ml of toluene. The combined filtrate and washings wereevaporated to give 68.0 g (83%) of product,3-methyl-5-oxo-1-cyclopentene-1-acetic acid ethyl ester as a pale yellowoil, bp 97°/0.05 mmHg, which is relatively unstable and should berefrigerated under nitrogen. The product was used in Example 10.

EXAMPLE 9

Alternative Isomerization Methods:

(1) A solution of 10 g of the product produced by Example 5 is placed in100 ml of pyridine and stirred under argon at 96° C. for 23.5 hours. Thesolvent (pyridine) was removed in vacuo at 45° C. to give 10 g of3-methyl-5-oxo-1-cyclopentene-1-acetic acid ethyl ester with a purity of96% as ascertained by high-pressure liquid chromatography.

(2) A solution of 1 g of the product produced by Example 5 in 15 ml oftoluene containing 100 mg 4-dimethylaminopyridine was boiled underreflux for 20 hours. The resulting mixture was cooled to roomtemperature and washed with 15 ml of 1 N hydrochloric acid, followed bytwo washes with water. The organic phase was dried over magnesiumsulfate, and evaporated to give 960 mg of3-methyl-5-oxo-1-cyclopentene-1-acetic acid ethyl ester.

EXAMPLE 10

Steps 5 and 6:

A 500-mL, round-bottomed flask was charged with 30.4 g (0.167 M) of3-methyl-5-oxo-1-cyclopentene-1-acetic acid ethyl ester (as prepared inExample 7 or 8), 122 mL of nitromethane, and 11.7 ml of Triton B. Themixture was stirred under nitrogen at 65°-70° C. for 2 hours, cooled to10° C., and acidified with 23 ml of cold (10° C.) 4 N H₂ SO₄ ; stirringwas continued for a further 30 minutes. The mixture was poured into 115ml of saturated brine and extracted with 230 ml of ether. The extractwas washed with saturated brine until it was neutral, dried with MgSO₄,and evaporated to give 43 g of crude product,3-methyl-2-(nitromethyl)-5-oxo-cyclopentane acetic acid ethyl ester, asan amber colored oil.

Crude 3-methyl-2-(nitromethyl)-5-oxo-cyclopentane acetic acid ethylester was added to a 1-L, round-bottomed flask equipped with amechanical stirrer, thermometer, and a nitrogen inlet tube. 355 ml of 1N NaOH was added, and the mixture was stirred at 40° C. under nitrogenfor 30 minutes. The mixture was cooled to room temperature and extractedwith 150 ml of CH₂ Cl₂, which was discarded. The aqueous phase wascooled to 10° C., acidified with 365 ml of cold (10° C.) lN HCl,extracted with three 200-ml portions, a total of 600 ml of ethylacetate, and dried (MgSO₄). To this was added 10 g of neutraldecolorizing charcoal; the mixture was then slurried for a few minutesand filtered over diatomaceous earth. Evaporation of the filtrate invacuo at less than 30° C. gave 37.4 g of4-alpha-methyl-3-beta-nitromethyl-2-alpha-carboxymethylcyclopentanone aspale yellow crystals which was dissolved, with stirring in 90 ml of hotethyl acetate-hexane, to produce upon filtration, 23 g (64%) of4-alpha-methyl-3-beta-nitromethyl-2-alpha-carboxymethyl cyclopentanoneas off-white crystals, mp 113°-114° C.

EXAMPLE 11

Resolution of (±)-Acid:

To a stirred heterogeneous mixture of 4.3 g (0.02 M) of4-alpha-methyl-3-beta-nitromethyl-2-alpha-carboxymethyl cyclopentanonein 60 ml of methylene chloride was added 7.0 g (0.021 M) of strychnineunder nitrogen; after about 10 minutes of stirring a homogeneoussolution was obtained. The mixture was stirred, under N₂, for 2 hours,concentrated in vacuo (bath temperature) less than 30° C., preferably25° C., and to the resulting gum (containing 5-10 ml of Ch₂ Cl₂) 60 mlof acetone was added; the remaining CH₂ Cl₂ was then evaporated invacuo. The mixture was vigorously stirred at room temperature for 30minutes and the salt of the undesired (+) acid removed by filtration; itwas washed with two 30-ml portions, a total of 60 ml of acetone. Thecombined filtrate and washings were evaporated in vacuo (temperatureless than 30° C.) to give 5.3 g of a gum, which was dissolved in 100 mlof ethyl acetate. Any insoluble material present was being removed byfiltrations, washed with four 100-ml portions of a total of 400 ml ofcold (15° C.) hydrochloric acid. The aqueous washes were back extractedwith 100 ml of ethyl acetate and the combined extracts washed with two100-ml portions of a total of 200 ml of water (until neutral), driedwith MgSO₄, and evaporated in vacuo (-30° C.) to give an oil. This oilwas dissolved in 5 ml of ethyl acetate and diluted with 5 ml of hexane.The resulting solution was left at -10° C. overnight and the crystallineracemic acid (470 mg) removed by filtration. Evaporation of the filtratein vacuo (-30° C.) gave an oil, which was kept under high vacuum (0.1mm/25° C.) overnight to give 1.7 g (79.5% yield) of [1R-1 alpha, 2 beta,3 alpha)]-2 -(nitromethyl)-3-methyl-5-oxo-1-cyclopentane acetic acid,.This crude material was used directly in the reduction and lactonizationto give3,3AR,4,5,6,6AS-hexahydro-4S-nitromthyl-5R-methyl-2H-cyclopenta[B]furan-]-one.

The above crude acid was crystallized from hexane to produce colorlesscrystals by filtration of [1R-(1 alpha, 2 beta, 3alpha)]-2-(nitromethyl)-3-methyl-5-oxo-1-cyclopentane acetic acid, mp56°-38° C.

What is claimed is:
 1. A compound of the formula: ##STR6## wherein Rrepresents hydrogen or a lower alkyl.
 2. The compound of claim 1 whereinR is methyl, ethyl or n-butyl.
 3. The compound of claim 1 wherein saidcompound is alpha-hydroxy-4-methyl-2-oxocyclopentane acetic acid butylester.
 4. The compound of claim 1 wherein said compound isalpha-hydroxy-4-methyl-2-oxocyclopentane acetic acid ethyl ester.